Brief general overview of hepatitis C virus
After the development of diagnostic tests for hepatitis A virus and hepatitis B virus, an additional agent, which could be experimentally transmitted to chimpanzees [Alter et al., Lancet 1, 459-463 (1978); Hollinger et al., Intervirology 10, 60-68 (1978); Tabor et al., Lancet 1, 463-466 (1978 )], became recognized as the major cause of transfusion-acquired hepatitis. cDNA clones corresponding to the causative non-A non-B (NANB) hepatitis agent, called hepatitis C virus (HCV), were reported in 1989 [Choo et al., Science 244, 359-362 (1989 )]. This breakthrough has led to rapid advances in diagnostics, and in our understanding of the epidemiology, pathogenesis and molecular virology of HCV (see Houghton et al., Curr Stud Hematol Blood Transfus 61, 1-11 (1994) for review). Evidence of HCV infection is found throughout the world, and the prevalence of HCV-specific antibodies ranges from 0.4-2% in most countries to more than 14% in Egypt [Hibbs et al., J. Inf. Dis. 168, 789-790 (1993)]. Besides transmission via blood or blood products, or less frequently by sexual and congenital routes, sporadic cases, not associated with known risk factors, occur and account for more than 40% of HCV cases [Alter et al., J. Am. Med. Assoc. 264, 2231-2235 (1990); Mast and Alter, Semin. Virol. 4, 273-283 (1993)]. Infections are usually chronic [Alter et al., N. Eng. J. Med. 327, 1899-1905 (1992)], and clinical outcomes range from an inapparent carrier state to acute hepatitis, chronic active hepatitis, and cirrhosis which is strongly associated with the development of hepatocellular carcinoma.
Although interferon (IFN)-.alpha. has been shown to be useful for the treatment of a minority of patients with chronic HCV infections [Davis et al., N. Engl. J. Med. 321, 1501-1506 (1989); DiBisceglie et al., New Engl. J. Med. 321, 1506-1510 (1989)] and subunit vaccines show some promise in the chimpanzee model [Choo et al., Proc. Nat. Acad. Sci. USA 91, 1294-1298 (1994)], future efforts are needed to develop more effective therapies and vaccines. The considerable diversity observed among different HCV isolates [for review, see Bukh et al., Sem. Liver Dis. 15, 41-63 (1995)], the emergence of genetic variants in chronically infected individuals [Enomoto et al., J. Hepatol. 17, 415-416 (1993); Hijikata et al., Biochem. Biophys. Res. Comm. 175, 220-228 (1991); Kato et al., Biochem. Biophys. Res. Comm. 189, 119-127 (1992); Kato et al., J. Virol. 67, 3923-3930 (1993); Kurosaki et al., Hepatology 18, 1293-1299 (1993); Lesniewski et al., J. Med. Virol. 40, 150-156 (1993); Ogata et al., Proc. Natl. Acad. Sci. USA 88, 3392-3396 (1991); Weiner et al., Virology 180, 842-848 (1991); Weiner et al., Proc. Natl. Acad. Sci. USA 89, 3468-3472 (1992)], and the lack of protective immunity elicited after HCV infection [Farci et al., Science 258, 135-140 (1992); Prince et al., J. Infect. Dis. 165, 438-443 (1992)] present major challenges towards these goals.